Available online http://arthritis-research.com/content/6/6/237 Introduction James Fries and Eswar Krishnan have recently presented an interesting argument for the proposition that ‘equip
Trang 1Available online http://arthritis-research.com/content/6/6/237
Introduction
James Fries and Eswar Krishnan have recently presented
an interesting argument for the proposition that ‘equipoise
is a false and diverting principle’ and propose an
alternative test of the ethics of a randomised controlled
trial, the ‘positive expected value’ test [1] The concept of
equipoise has been introduced into the medical literature
on many occasions [2–7] Both concepts are intended to
give ethical justification to entering patients into
randomised controlled trials The problem that critics of
such trials pose is that entering a patient into a trial seems
to involve knowingly failing to offer the patient the
treatment the doctor believes to be best for the patient, in
the interests of scientific research and future patients
However, if there is genuine uncertainty as to which of the
treatments being compared is superior, then randomised
assignment can be justified [8] There is considerable
debate in the literature about how to give rigorous
expression to what ‘genuine uncertainty’ requires How
much uncertainty? Whose uncertainty? When should we
stop being ‘uncertain’ and start being ‘certain’? The
concepts of ‘equipoise’ defined in this literature are all
attempts to give more precise expression to what is meant
by ‘uncertainty’ here, and to give a sound basis to the
ethical justification of randomisation in controlled trials
Design bias
Fries and Krishnan argue that in the context of licensing trials of new drugs these debates are irrelevant and misleading They argue that new drugs that reach industry-sponsored phase III trials are more likely to be effective than not, because they reach this stage of testing only if they have survived rigorous preclinical and clinical screening, and because the trial design decisions that are taken are those most likely to produce a positive result They argue that this is demonstrated by the fact that all the trials they reviewed produced positive results
in favour of the new drugs being tested [1] On the basis
of this, they argue that equipoise is being systematically violated
Their empirical argument is not strong methodologically, and they acknowledge that there are alternative
explanations for their finding In addition, their ex post
finding that all the trials they reviewed gave positive results
does not entail that ex ante the triallists were not
substantially uncertain that they would gain a positive result Nevertheless, their qualitative argument for the existence of ‘design bias’ is plausible The question is: what follows from this?
Commentary
Ethics of randomised controlled trials – not yet time to give up
on equipoise
Richard E Ashcroft
Medical Ethics Unit, Imperial College London, London, UK
Corresponding author: Richard E Ashcroft, r.ashcroft@imperial.ac.uk
Published: 14 September 2004
Arthritis Res Ther 2004, 6:237-239 (DOI 10.1186/ar1442)
© 2004 BioMed Central Ltd
Abstract
In this commentary on Fries and Krishnan’s argument that ‘design bias’ undermines the status of
equipoise as the ethical justification for randomised controlled trials, it is argued that their argument is
analogous to Bayesian arguments for the use of informative priors in trial design, but that this does not
undermine the importance of equipoise In particular, mismatches between the outcomes of interest to
industrial sponsors of research and outcomes of interest to patients and clinicians ensure that in many
cases industry-sponsored trials can fail to reflect the reasonable equipoise of working clinicians
Keywords: design bias, ethical principles, expected outcomes, randomised controlled trials
Trang 2Arthritis Research & Therapy Vol 6 No 6 Ashcroft
Design bias and the Bayesians
One response is to argue that the Fries–Krishnan
argument is nothing new, because in effect the Bayesians
have been arguing something similar for years Some
Bayesian philosophers argue that randomisation is
unnecessary in the first place, and on that basis
randomised controlled trials are unethical [9,10] Most
Bayesian statisticians and triallists, however, do accept
that randomisation has its place in trial design [11,12]
What is required, they say, is that one starts with an
‘informative prior’ that fixes the rate at which people are
initially randomised to different arms of the trial On this
account, something like equipoise or uncertainty remains
the ethical justification for randomisation The concepts of
equipoise normally used are qualitative (one is either
uncertain, or not, or the community at large is uncertain or
not) Here the concept used is quantitative (one specifies
a degree of belief in the proposition that the new drug is
safe or effective, and a range of degree of belief within
which one is ‘uncertain’ as to the truth or falsity of that
proposition) [13]
As Fries and Krishnan argued, and as most Bayesians also
accept, this approach to the decision to run a trial, and to
design in it a particular way, involves subjective
judgements about what is important and about what it is
fair to offer patients This then involves placing weight not
only on what clinicians believe, and on what they think is
important, but also on what patients believe and think
important [5,14,15]
Problems with the Fries–Krishnan–Bayesian
approach
One response to the claim that phase III trials are
systematically prone to design bias is the following
Suppose that any new drug in phase III trials is likely to
work, at least to some extent The primary purpose of such
a trial cannot then be to determine whether or not the new
drug is effective Instead, it is to measure how effective it
is, and, secondly, to identify any problems with using the
drug in clinical practice (rare adverse events, the
tolerability of known side-effects, adherence to treatment,
quality-of-life issues) If this is the purpose of phase III
trials, then this will mean that different types of design and
different numbers of patients will be required in many
cases than are now required for trials that aim at proving
effectiveness alone This may have the effect of
undermining ‘design bias’ If the origin of design bias is
sponsors selecting the design that will put their new
product in the best light, then this represents a constraint
on the designs they are entitled to choose
Developing this, admittedly speculative, thought, even
within the Bayesian approach there is considerable
complexity Designs that make full use of the ability to alter
the assignment of patients to arms of the trial in the light of
new information can be complex and difficult to analyse, and the choice of prior to reflect the different degrees of belief of sceptics or enthusiasts in the clinical and patient communities can be controversial [12,13,16] Designing a trial that reflects the triallists’ confidence in the new product, while allowing a fair test of that product, which produces results that can be understood by, and can hence persuade, the clinician who is neutral about the new product is harder than it looks Fries and Krishnan might object that if design bias is endemic, then the clinician ought not to be neutral about new products; this is
a very strong claim to make, however, and I will return to it The next problem is that a design chosen to present the new drug in as favourable a light as possible may well not
be the design that answers the question that is clinically relevant [17] They may measure the ‘wrong’ outcomes or make the ‘wrong’ comparisons Clinicians may be interested in the relative effectiveness of drug versus surgery for osteoarthritis of the knee, yet they are offered very little evidence on this type of question; patients may
be more interested in mobility than in pain control, but mobility may not be used as an outcome measure [18,19] Consider, therefore, the clinician who is not involved directly with the drug development but is interested in either participating in the trial, or (later on) in using the results of the trial to inform her practice On the Fries–Krishnan view, she ought to have a prior degree of belief in favour of the new product’s effectiveness Other things being equal, she seems to be being asked to consider any new drug as an advance – otherwise why would the drug company put all its effort into developing it? Yet the reasonably experienced clinician will know that new drugs are not always advances on the existing pharmacopoeia, will not always give patients outcomes they prefer, and may sometimes be harmful or ineffective
in practice So how enthusiastic ought the clinician to be? The reasonable patient deserves to be informed by his clinician about new products and new trials, but also about the ins and outs of such products and such trials In practice, these considerations would lead clinicians and patients towards something very like equipoise, save in those happy situations in which there is close concordance between the interests of patients, clinicians, triallists and sponsors
Conclusions
Fries and Krishnan are certainly correct in arguing that the equipoise concept has serious problems Yet it is not the case that it is dead in the water For practical clinical purposes it remains the central test of the ethical justification for randomisation They are also correct to stress the role of patient autonomy and patient preferences in the design and conduct of trials What they establish is that equipoise is neither a necessary nor a
Trang 3sufficient condition for a trial to be justified Some trials do
not require equipoise, and not all trials with equipoise are
ethically justified For example, phase I and II trials are
rarely based on equipoise, and some trials in chronic
illness or in non-serious acute illness can be conducted
with placebo control even when there is an effective
standard therapy, provided that the patients consent and
are really free to choose the alternatives [20] Some trials
of potentially life-saving treatments, to which there is no
effective alternative, are arguably unethical if patients have
no choice but to enter the trial [21] Patient autonomy is
surely very important
But the point of the equipoise principle is that doctors
need to be able to assure themselves and their patients
that the offer of randomisation is not suboptimal The
defect of the Fries–Krishnan claim (that trials can be
ethical if there is positive expected benefit) is that this
need not be maximal: doctors, on this theory, can
knowingly and willingly do less than their best for their
patients The point of the equipoise theory was that it
seeks to show how randomisation can be consistent with
seeking to do one’s best for one’s patient Although
conceptual problems remain to be resolved with
equipoise, the ethical costs of giving up on it as the
default justification are high [4,5,7] It may be that we will
eventually find a better justification for trials than
equipoise, but I am not convinced that ‘design bias’ is a
sufficient reason to give up on equipoise just yet
Competing interests
The author declares that he has no competing interests
Acknowledgements
I thank Ainsley Newson for commenting on a draft of this paper.
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Available online http://arthritis-research.com/content/6/6/237